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TIPE3 represses head and neck squamous cell carcinoma progression via triggering PGAM5 mediated mitochondria
Wei Chen1,2,3, Xijuan Chen1,2,3, Lixuan Wang1,2,3
1Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, 510055, China.
Abstract:
Mitochondria are essential organelles in balancing oxidative stress and cell death during cancer cell proliferation. Rapid tumor growth induces tremendous stress on mitochondria. The mammalian tumor necrosis factor-α-induced protein 8-likes (TIPEs) family plays critical roles in balancing cancer cell death and survival. Yet, the roles of TIPEs in HNSCC tumorigenesis and mitochondria stress maintenance is unclear. Based on an integrative analysis of public HNSCC datasets, we identified that the downregulation of TIPE3 via its promoter hypermethylation modification is the major event of TIPEs alterations during HNSCC tumorigenesis. Low expression levels of TIPE3 were correlated with high malignancy and poor clinical outcomes of HNSCC patients. Restoring TIPE3 represses HNSCC proliferation, migration, and invasion in vitro and in vivo, while silencing TIPE3 acted on an opposite way. Mechanistically, TIPE3 band to the PGAM5 and electron transport chain (ETC) complex. Restoring TIPE3 promoted PGAM5 recruiting BAX and dephosphorylating p-DRP1(Ser637), which triggered mitochondrial outer membrane permeabilization and fragmentation. Ultimately, TIPE3 induced ETC damage and oxygen consumption rate decrease, ROS accumulation, mitochondrial membrane potential depolarization, and cell apoptosis. Collectively, our work reveals that TIPE3 plays critical role in maintaining mitochondrial stress and cancer cell progression in HNSCC, which might be a potential therapeutic target for HNSCC patients.
Insights
Tumor necrosis factor-α-induced protein 8-like 3 (TIPE3) downregulation promotes head and neck squamous cell carcinoma (HNSCC) progression by impairing mitochondrial function. Restoring TIPE3 inhibits HNSCC growth and induces apoptosis, suggesting TIPE3 as a therapeutic target.
Area of Science:
- Oncology
- Mitochondrial Biology
- Cancer Cell Biology
Background:
- Mitochondria are crucial for managing oxidative stress and cell death in proliferating cancer cells.
- Tumor necrosis factor-α-induced protein 8-like (TIPE) family members regulate cancer cell survival and death.
- The specific roles of TIPEs in head and neck squamous cell carcinoma (HNSCC) tumorigenesis and mitochondrial stress remain largely unknown.
Purpose of the Study:
- To investigate the role of TIPE family members, particularly TIPE3, in HNSCC development and mitochondrial homeostasis.
- To elucidate the underlying molecular mechanisms by which TIPE3 influences HNSCC progression and mitochondrial function.
Main Methods:
- Integrative analysis of public HNSCC datasets to identify alterations in TIPEs.
- In vitro and in vivo experiments to assess the effects of TIPE3 restoration or silencing on HNSCC cells.
- Mechanistic studies involving protein-protein interactions (PGAM5, BAX, DRP1) and assessment of mitochondrial parameters (ETC, ROS, membrane potential, apoptosis).
Main Results:
- TIPE3 downregulation, driven by promoter hypermethylation, is a key event in HNSCC tumorigenesis.
- Low TIPE3 expression correlates with increased HNSCC malignancy and poorer patient outcomes.
- Restoring TIPE3 suppressed HNSCC proliferation, migration, and invasion; silencing TIPE3 had opposite effects.
- TIPE3 interacts with PGAM5 and the electron transport chain (ETC) complex, influencing BAX recruitment and DRP1 dephosphorylation.
- TIPE3 induction of mitochondrial dysfunction includes ETC damage, reduced oxygen consumption, ROS accumulation, and apoptosis.
Conclusions:
- TIPE3 plays a critical role in maintaining mitochondrial stress and regulating cancer cell progression in HNSCC.
- TIPE3 acts as a tumor suppressor in HNSCC by preserving mitochondrial integrity and function.
- TIPE3 represents a potential therapeutic target for HNSCC patients.
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